Acute myeloid leukemia (AML) is one of the most common forms of leukemia in adults and despite advances in treatment the 5 year survival is less than 20-50% in adults and significantly lower in the elderly. The remarkable success in treating one relatively uncommon subset of AML, acute promyelocytic leukemia, with all trans-retinoic acid (ATRA) illustrates the great promise for agents with greater efficacy and less toxicity. Utilizing ATRA, the presumed cure of 75-85% of patients is possible. ATRA?s remarkable success stems from the fact that AML is a disease characterized by the arrest of differentiation of immature myeloid cells. ATRA overcomes this block in differentiation by forcing leukemic cells to mature. Unfortunately, ATRA does not work clinically for 90-95% of AML patients. Recently we identified that targeting the kinase GSK3 is a promising strategy to induce AML differentiation, particularly in combination with ATRA. Unfortunately, there are no FDA approved specific GSK3 inhibitors. We have identified a highly potent and specific GSK3 inhibitor that exhibits promise against AML in cell and animal models. In this proposal, we will assess the pharmacologic properties of this GSK3 inhibitor, perform animal efficacy studies, and determine its effects on primary patient samples. It is hoped that this work will lead to a new differentiation therapy that can improve the prognosis of patients with non-APL leukemia.